Allergic asthma is characterized by exaggerated Th2 inflammation resulting from interaction between DC and T cells. Molecules acting in this interaction, regulating cell activation and differentiation are desirable therapeutic targets. This proposal aims to define the precise roles of two such molecules new to the lung immunobiology field - immune semaphorins Sema4A and Sema4D - in allergic airway inflammation as a first step towards using them as novel targets for asthma therapy. Sema4A and Sema4D belong to the Class IV semaphorin family proteins. Several recent studies have identified the expression of semaphorins on immune cells and have shown new roles for these molecules in immune cell differentiation and inflammation. In the immune system, Sema4A is preferentially expressed on immature DC and Sema4D on resting T cells. Their functional receptors, Tim-2 and CD72, are preferentially expressed on T cells and DC, respectively. Both immune semaphorins are upregulated with cell activation and play a critical and complex role in DC - T cell interaction. Our recent study shows tissue specific regulation of the expression of immune semaphorins and their receptors suggesting that Sema4A-Tim-2 interaction occurs rather in lymphoid tissues whereas Sema4D- CD72 interaction occurs in the lung and lymphoid tissues. We hypothesize that immune semaphorins play nonredundant critical costimulatory roles in lung local and secondary lymphoid tissue dendritic cell - T cell interaction, activation and function, thereby determining the allergic airway disease outcome. Two specific aims will test this hypothesis: 1) to determine the contribution of immune semaphorins to lung inflammation induced by allergen exposure (antigen-dependent model), and 2) to determine the contribution of immune semaphorins to vascular endothelial growth factor (VEGF)-induced allergic airway responses and enhanced respiratory sensitization (antigen-independent and -dependent model). This study will represent the first comprehensive analysis of immune semaphorins function in airway inflammation induced by either allergen, or VEGF, or by both. It will advance our understanding of the immunologic mechanisms underlying asthmatic disease onset and progression. Our long-term objective is to use the results from these studies to develop strategies to specifically modulate immune semaphorin expression and interaction with their receptors in order to ameliorate asthmatic lung disease. PUBLIC HEALTH RELEVANCE: This proposal is aimed to define the precise roles of two novel molecules for the asthma filed - immune semaphorins Sema4A and Sema4D - in allergic airway inflammation. As the role of immune semaphorins in allergic airway response has never been addressed previously, the proposed study will provide a new insight into the lung immune semaphorin biology and Th2 inflammatory response regulation. The new knowledge obtained from this study will be used for the development of an optimal strategy for asthma intervention.